In recent microdialysis studies, increased extracellular concentrations of taurine after high ethanol dose administration were identified in various rat brain regions. The mechanisms by which ethanol ... [more ▼]

In recent microdialysis studies, increased extracellular concentrations of taurine after high ethanol dose administration were identified in various rat brain regions. The mechanisms by which ethanol caused these increases in extracellular taurine concentration remained unclear but could be related to ethanol-induced cell swelling. The aim of the current study was to investigate whether changes in the body osmotic state modulate the effects of ethanol on brain extracellular taurine concentrations. In several groups of rats, brain hypoosmotic or hyperosmotic states were superimposed on acute ethanol (2.0-g/kg) injections, and extracellular taurine concentrations within the nucleus accumbens were assessed by using an intracerebral microdialysis procedure. A hypoosmotic state was obtained by systemic administration of water while hyperosmotic states were induced by intraperitoneal injections of hypertonic saline solutions (1.8% or 3.6% saline). In isoosmotic conditions, ethanol induced an immediate and significant increase in taurine microdialysate content, confirming results of previous studies. However, the effects of ethanol on taurine concentrations were modulated by osmotic manipulations. Hypoosmotic conditions significantly potentiated ethanol-induced taurine release. In contrast, ethanol-induced increases in extracellular taurine levels were attenuated by 1.8% saline injection and totally prevented by 3.6% saline administration. These results strongly argue in favor of a primary role, of osmoregulation in ethanol-induced taurine release. Ethanol-induced cell swelling probably activates volume-sensitive channels, and taurine passively diffuses outside the cells along its concentration gradient. (C) 2003 Elsevier Science Inc. All rights reserved. [less ▲]

Recent studies involved acetaldehyde, the first ethanol metabolite, in both the rewarding and aversive effects of ethanol consumption. Brain acetaldehyde is believed to originate mainly from local brain ... [more ▼]

Recent studies involved acetaldehyde, the first ethanol metabolite, in both the rewarding and aversive effects of ethanol consumption. Brain acetaldehyde is believed to originate mainly from local brain metabolism of ethanol by the enzyme catalase. Therefore, the inhibition of catalase by 3-amino-1,2,4-triazole (aminotriazole) may help to clarify the involvement of acetaldehyde in ethanol's hedonic effects. In the present study, multiple doses of both ethanol and aminotriazole were used to investigate the effects of catalase inhibition on ethanol-induced conditioned taste aversion (CTA). A separate microdialysis experiment investigated the effects of aminotriazole pretreatment on the time course of brain ethanol concentrations. Ethanol induced a dose-dependent CTA with a maximal effect after conditioning with 2.0 g/kg ethanol. Aminotriazole pretreatments dose-dependently potentiated the CTA induced by 1.0 g/kg ethanol. However, aminotriazole pretreatments did not alter the CTA induced by higher ethanol doses (1.5 and 2.0 g/kg) probably because a maximal aversion for saccharin was already obtained without aminotriazole. The results of the microdialysis experiment confirmed that the effects of aminotriazole cannot be attributed to local alterations of brain ethanol levels. The present study argues against a role for brain acetaldehyde in ethanol's aversive effects but in favor of its involvement in ethanol rewarding properties. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. [less ▲]

Rationale: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. Objectives: The present ... [more ▼]

Rationale: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. Objectives: The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. Methods: A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. Results: Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. Conclusions: The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA. [less ▲]

Acetaldehyde has been suggested to mediate a number of the pharmacological and behavioural effects of ethanol. Recently, several studies investigated the role of acetaldehyde in the subjective effects of ... [more ▼]

Acetaldehyde has been suggested to mediate a number of the pharmacological and behavioural effects of ethanol. Recently, several studies investigated the role of acetaldehyde in the subjective effects of ethanol, but obtained conflicting results. With the discriminative taste aversion (DTA) procedure, high acetaldehyde doses were shown to substitute for the discriminative stimulus effects of ethanol. In contrast, the operant drug discrimination protocol failed to show any substitution effect of acetaldehyde. Several methodological differences between the two procedures could explain these discrepancies, and particularly the absence of an individual discrimination criterion in the DTA procedure. In the present study, the DTA procedure was adapted to introduce such a criterion. In addition, the effects of acetaldehyde were compared with those of other drugs, for which the substitution effects for ethanol are well known. Rats were trained to discriminate 1.0 g/kg ethanol from saline in a DTA protocol. When the rats met the criterion of ethanol discrimination, various doses of several drugs were tested for their ethanol stimulus substitution effects: ethanol, acetaldehyde, dizocilpine, diazepam and nicotine. The results showed a clear dose-dependent discrimination of ethanol stimulus effects. In addition, dizocilpine fully substituted for ethanol, while diazepam only partially substituted. In contrast, both acetaldehyde and nicotine failed to substitute for ethanol. These results show that acetaldehyde is not significantly involved in the subjective and discriminative stimulus effects of ethanol. Acetaldehyde up to toxic doses did not substitute for the ethanol discriminative stimulus in the DTA protocol, when non-specific effects were carefully controlled. [less ▲]

Rationale. In drug discrimination procedures, the substitution pattern for ethanol of various receptor ligands is dependent upon ethanol training dose, presumably reflecting functionally different concentrations of ethanol in the brain. The discriminative stimulus effects of ethanol are also time-dependent, although very few studies have investigated the time course of ethanol discriminations. Objectives. The present study investigated the relationship between brain ethanol concentrations (BrEC), as measured by intracranial microdialysis of the nucleus accumbens, and the time course of ethanol discriminative effects. Methods. Two groups of rats were trained to discriminate either 1.0 or 2.0 g/kg ethanol from water following a 30-min post-ethanol interval. Following training, the time course of the discriminative stimulus was assessed using a series of abbreviated testing trials at 20-min intervals for 5 h after the administration of various ethanol doses (0, 0.5, 1.0 and 2.0 g/kg). The rats were then fitted with microdialysis probes and the time course of BrECs were determined under conditions similar to the behavioral assessments. Results. BrECs were significantly above zero at 4 min post-gavage and attained peak concentrations of 16 mmol/l, 24 mmol/l and 42 mmol/l at 9 min, 16 min and 95 min after IG administration of 0.5, 1.0 and 2.0 g/kg ethanol, respectively. BrECs were similar in ethanol-naive and ethanol-trained rats, indicating a lack of pharmacokinetic tolerance under these discrimination procedures. The discriminative stimulus effects of ethanol were dose- and time-dependent, with a threshold concentration of approximately 12 mmol/l achieved at 5 min after 1.0 g/kg ethanol gavage in rats trained to discriminate 1.0 g/kg ethanol. Acute tolerance to the discriminative stimulus effects of ethanol was evident from BrECs 2-5 h post-ethanol gavage. Conclusions. Ethanol given intragastrically results in a rapid increase in BrEC, independent of ethanol exposure history. The discriminative stimulus effects of ethanol trained at 30 min post-gavage reflect a specific range of BrEC, and depend on the training dose. These data suggest that qualitatively different stimulus effects of ethanol reflect both different ranges of BrEC, as well as within dose acute tolerance to the discriminative stimulus effects. [less ▲]

Acetaldehyde, the first ethanol metabolite, was recently suggested to play a major role in many behavioral effects of ethanol. However, no studies have directly investigated the behavioral effects of ... [more ▼]

Acetaldehyde, the first ethanol metabolite, was recently suggested to play a major role in many behavioral effects of ethanol. However, no studies have directly investigated the behavioral effects of acetaldehyde after acute administration. Therefore, the aim of the present study was to characterize the locomotor, hypnotic and ataxic effects of acetaldehyde in C57BL/6J mice. Various acetaldehyde doses (0-300 mg/kg) were injected intraperitoneally and their effects were investigated with several classical behavioral tests. The locomotor effects of acetaldehyde were measured in standard activity boxes. In addition, the loss of righting reflex was used to assess the hypnotic effects of acetaldehyde. Finally, the ataxic effects of acetaldehyde were studied with the horizontal wire test. The results show that acetaldehyde induced a significant hypolocomotor effect at 170 mg/kg and higher doses. In addition, the hypnotic effects of acetaldehyde were evidenced by a loss of righting reflex in doses between 170 and 300 mg/kg. However, the locomotor and hypnotic effects of acetaldehyde were very brief relative to what is observed after ethanol administration. After 170 mg/kg acetaldehyde, normal activity was recovered in less than 30 minutes and the loss of righting reflex lasted only an average of 6.14 ± 1.29 minutes after the administration of 300 mg/kg acetaldehyde, the highest testable dose before lethality. Ataxic effects were observed with lower doses that did not significantly affect locomotor activity. These results show that acetaldehyde, like ethanol, possesses sedative, hypnotic and ataxic properties and therefore indicate that the first product of ethanol metabolism might be involved in these ethanol effects. [less ▲]

It has been postulated that a number of central effects of ethanol are mediated through the action of its first metabolite, acetaldehyde. In particular, acetaldehyde might be involved in the anxiolytic ... [more ▼]

It has been postulated that a number of central effects of ethanol are mediated through the action of its first metabolite, acetaldehyde. In particular, acetaldehyde might be involved in the anxiolytic and hedonic effects of ethanol and is therefore believed to play an important role in alcohol abuse. In agreement with this assumption, previous studies indicated that acetaldehyde is mainly reinforcing in rats, which have been shown to readily self-administer acetaldehyde both peripherally and centrally. However, the hedonic effects of acetaldehyde have never been tested in mice, and the possible amnesic and anxiolytic effects of acetaldehyde remain to be elucidated. Therefore, the present studies were aimed at characterizing the anxiolytic, hedonic and amnesic effects of acetaldehyde after its acute peripheral administration to C57BL/6J mice. The effects of intraperitoneal acetaldehyde (0-300 mg/kg) injections were assessed in several classical behavioral tests. The anxiolytic effects were tested with the elevated plus maze, the hedonic effects with the place conditioning procedure and the amnesic effects with the passive avoidance apparatus. Our results show that acetaldehyde dose-dependently altered memory consolidation as evidenced by a reduced performance in the passive avoidance test when acetaldehyde was injected immediately after training at doses between 100 and 300 mg/kg. The elevated plus-maze showed that acetaldehyde, in contrast to ethanol, does not possess anxiolytic properties. Finally, the results of the place conditioning experiment confirmed that acetaldehyde displays significant hedonic properties. The present results add further support to the role of acetaldehyde in ethanol amnesic and hedonic effects but interestingly suggest that acetaldehyde is not involved in ethanol anxiolytic effects. [less ▲]

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions, However, these studies led to conflicting results, suggesting that ... [more ▼]

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions, However, these studies led to conflicting results, suggesting that individual differences between rat strains and lines may play an important role. In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to investigate the possible relationship between ethanol sensitivity and the concentrations of extracellular amino acids in the nucleus accumbens. Several groups of HAS and LAS rats were injected with either saline or ethanol (1.0, 2.0 or 3.0 g/kg, i.p.) and the concentrations of amino acids in the nucleus accumbens microdialysates were assayed by electrochemical detection. Acute ethanol induced a dose-dependent increase in extracellular taurine concentrations. However, this increase was significantly reduced at 2,0 and 3.0 g,,kg ethanol in HAS rats relative to LAS rats. Since the biological functions of taurine suggest its implication in the reduction of ethanol adverse effects, a higher increase in taurine concentrations may contribute to the lower ethanol sensitivity of LAS rats. Although 2.0 and 3.0 g/kg ethanol did not affect extracellular glutamate concentrations, a significant increase in glutamate was observed after 1.0 g/kg ethanol to HAS rats but not to LAS rats. Such an effect remains unexplained but suggests that discrepancies between the results of previous microdialysate studies may be related to differences in the ethanol sensitivities of various rat strains. (C) 2002 Elsevier Science B.V All rights reserved. [less ▲]

Background: Acetaldehyde has been suggested to mediate some of the effects of ethanol. Acetaldehyde can be produced by the enzyme catalase within the brain after ethanol administration. The catalase ... [more ▼]

Background: Acetaldehyde has been suggested to mediate some of the effects of ethanol. Acetaldehyde can be produced by the enzyme catalase within the brain after ethanol administration. The catalase inhibitor 3-amino-1,2,4-triazole (AT) reduces the production of acetaldehyde, and AT administration can reduce a number of ethanol-induced behavioral effects; this suggests the involvement of acetaldehyde in these behaviors. However, a role for acetaldehyde in mediating the discriminative stimulus effects of ethanol remains unclear. Methods: The contribution of acetaldehyde to the discriminative stimulus effects of ethanol was investigated by use of a two-lever drug discrimination paradigm with food reinforcement. Male Long-Evans rats were trained to discriminate water from either 1.0 or 2.0 g/kg ethanol. Stimulus substitution tests were conducted with ethanol (0 –2.5 g/kg by gavage) and acetaldehyde (0–300 mg/kg intraperitoneally). A cumulative dose-response procedure was then used to investigate the effects of pretreatments with AT (0.5 and 1.0 g/kg intraperitoneally) on ethanol discrimination. Results: Acetaldehyde up to doses that decreased response rates (300 mg/kg) did not substitute for the discriminative stimulus effects of 1.0 or 2.0 g/kg ethanol. In addition, AT pretreatment did not affect the dose-response curves for ethanol discrimination. Conclusions: These results show that exogenous acetaldehyde administration does not produce discriminative stimulus effects that are similar to those of ethanol. Also, pretreatment with the catalase inhibitor did not affect the dose-response curve for ethanol discrimination, and this suggests that endogenously produced acetaldehyde does not contribute to the discriminative stimulus effects of ethanol. Together these results suggest that acetaldehyde does not mediate the discriminative stimulus effects of 1.0 to 2.0 g/kg ethanol. [less ▲]

Rationale: Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of ... [more ▼]

Rationale: Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of environmental stimuli previously associated with ethanol administrations. This action is believed to contribute to the clinical benefits of acamprosate treatment in alcoholics. Objectives: In the present experiment, a classical drug-conditioning paradigm was used to test whether acamprosate modulates the effects of ethanol-paired environmental stimuli on spontaneous motor activity. Methods: Wistar rats were divided into three groups: cued, uncued and control. The cued group daily received ethanol injections (2.0 g/kg, IP) in a specific testing environment. The uncued group daily received ethanol injections (2.0 g/kg, IP) in their home cage but never experienced ethanol in the testing environment. The control group was injected with saline and never experienced ethanol. After 8 conditioning days, the rats were IP injected with various ethanol doses (saline, 1.0, 1.5 or 2.0 g/kg) and their spontaneous motor activity in the testing environment was recorded to investigate their respective tolerance to ethanol inhibitory effects. In the second part of the study, the same procedure was repeated with chronically acamprosate-treated rats. The chronic acamprosate treatment (400 mg/kg per day) started 2 weeks before the conditioning procedure by diluting acamprosate in the drinking bottles and was maintained throughout the whole experiment. Results: The cued rats showed a significant environment-dependent tolerance to ethanol inhibitory effects relative to the uncued and control rats. This higher ethanol tolerance of the cued rats was mainly due to a faster recovery from ethanol's inhibitory effects on spontaneous activity. Furthermore, the cued rats showed a higher level of activity in the testing environment after the saline injection. However, it is not clear whether this hyperactivity is a conditioned compensatory response or an increased exploratory behavior. Acamprosate totally abolished the environment-dependent tolerance to ethanol, whereas it did not alter the hyperactivity of the cued rats in the testing environment. Conclusions: The results of the present study suggest that acamprosate reduces ethanol-conditioned effects. Such an action may be of importance to explain the anti-relapse effects of acamprosate. [less ▲]

in Proceedings of the 22nd European Winterconference on Brain Research (2002)

The withdrawal syndrome is closely related to the concepts of tolerance and physical dependence. The chronic consumption of a drug is believed to induce adaptive changes that are designed to oppose the ... [more ▼]

The withdrawal syndrome is closely related to the concepts of tolerance and physical dependence. The chronic consumption of a drug is believed to induce adaptive changes that are designed to oppose the acute effects of the drug. Such adaptive changes increase the tolerance to acute drug effects but lead to physical dependence, which is revealed by withdrawal symptoms when the drug is cleared from the body. However, another form of adaptive response to repeated drug consumption has been identified. This adaptive response appears after the intermittent repeated administration of a drug in association with the same set of environmental stimuli. After several associations, these environmental stimuli become able to induce a conditioned adaptive response. Such response leads to the phenomenon of “environment-dependent tolerance” that was observed with many drugs of abuse. However, if the drug is not administered, the conditioned stimuli alone may induce a “conditioned withdrawal syndrome”. Although less studied than the classical withdrawal syndrome, this conditioned withdrawal syndrome may be of importance for the development of drug dependence. In our experiments, we have studied the development of a conditioned withdrawal syndrome after repeated associations of a specific set of environmental stimuli with ethanol injections in Wistar rats. After repeated administrations of ethanol, the rats showed a clear environmental-dependent tolerance to ethanol. Furthermore, these conditioned stimuli induced behavioral (hyperexcitation) and neurochemical (increase glutamate release) responses similar to those observed after chronic alcohol withdrawal. [less ▲]

It is known that ethanol administration inhibits the acoustic startle response, but whether this sensitivity varies within-session has not been investigated. The purpose of the present study was to ... [more ▼]

It is known that ethanol administration inhibits the acoustic startle response, but whether this sensitivity varies within-session has not been investigated. The purpose of the present study was to compare the time-course of ethanol levels in brain with alterations in the acoustic startle response. Three experiments were conducted in adult male Sprague-Dawley rats. 1) Ethanol concentrations in brain were determined by microdialysis following the acute administration of 0.3, 1.0 and 3.0 g/kg ig of ethanol. 2) The effect of ethanol on the acoustic startle response was determined after the same doses. 3) The acoustic startle response was determined during two time periods, at 2-18 and 30-46 minutes, after ethanol administration to evaluate periods of ascending and descending ethanol levels. In expt. 1, brain levels of ethanol rose rapidly, peaking within 4-8 minutes following all doses. In expt. 2, ethanol administration reduced the acoustic startle response in a dose-related manner; all doses significantly reduced the response. In expt. 3, prepulse inhibition was diminished by ethanol during a very short period immediately after ethanol administration, whereas the acoustic startle response was inhibited only during later times. These data indicate that the acoustic startle response was exquisitely sensitive to ethanol, even at doses as low as 0.3 g/kg. In addition, prepulse inhibition was selectively disrupted immediately after ethanol administration, which suggests that this phenomenon may accompany the short-lived ascending limb of the brain ethanol curve. Supported by AA 12356 (DL) and AA11997. [less ▲]

Acetaldehyde, the first ethanol metabolite, has been suggested to mediate some of the behavioral effects of ethanol and particularly its reinforcing properties, although this later hypothesis remains ... [more ▼]

Acetaldehyde, the first ethanol metabolite, has been suggested to mediate some of the behavioral effects of ethanol and particularly its reinforcing properties, although this later hypothesis remains extremely controversial. While several studies demonstrated the reinforcing effects of brain acetaldehyde, blood acetaldehyde accumulation is believed to be primarily aversive. In the present study, a conditioned reinforcement procedure has been used to investigate the reinforcing and/or aversive effects of intraperitoneal injections of both acetaldehyde and ethanol in Wistar rats. An olfactory stimulus was paired with daily injections of either ethanol (0, 0.25, 0.5, 1 and 2 g/kg) or acetaldehyde (0, 10, 20, 100 and 150 mg/kg). After eight conditioning sessions, all rats were tested for their stimulus preference or aversion. The results show that conditioning with small, 0.25 and 0.5 g/kg, ethanol doses induced neither preference nor aversion for the olfactory cue. In contrast, higher ethanol doses (1.0 and 2.0 g/kg) resulted in significant stimulus aversions. Acetaldehyde conditioning led to a biphasic stimulus preference, with a maximal preference around 20 mg/kg acetaldehyde. No evidence of aversive effects was found with increasing doses of acetaldehyde, even with concentrations close to the lethal limit. The present study clearly shows that systemic acetaldehyde injections induced significant stimulus preferences. This suggests that acetaldehyde may be, at least in part, responsible for the reinforcing effects of alcohol intake. [less ▲]